Bladder cancer (BlCa) is one of the leading causes of cancer-related morbidity and mortality. Global estimates for 2002 indicate that approximately 357,000 bladder cancer cases were diagnosed and that approximately 145,000 patients succumbed to the disease (GLOBOCAN 2002: Cancer Incidence, Mortality, and Prevalence Worldwide; IARC Cancerbase No. 4, v. 2.0 ed. Lyon: IARCPress (2004)). In the USA, bladder cancer is the second most common genitourinary (GU) malignancy, with about 71,000 new cases and more than 14,000 deaths in 2009 (Jetnal et al. (2009) CA Cancer J Clin. 59:225-249). The incidence of BlCa increases with age, with an average age at the time of diagnosis in the 60 s, and it is three times more common in men than in women (Kaufman et al. (2009) Lancet 374:239-249). Although several risk factors (e.g., smoking habits and exposure to carcinogens) have been identified, effective strategies for early detection are still not available (Mitra et al. (2009) Ann. Rev. Pathol. 4:251-285).
The present gold standard strategy for BlCa diagnosis is non-invasive voided urine cytology, followed by cystoscopic examination. However, both methods have low sensitivity, especially for low grade tumors (Kaufman et al (2009) Lancet 374:239-249). Several BlCa markers were recently reviewed by Vrooman and Witjes (Vrooman et al. (2008) Eur. Urol. 53:909-916; herein incorporated by reference in its entirety), but were found to be unsuitable for clinical use due to low predictive power and high cost compared with routine urinary cytology. Additional tests have as yet failed to yield diagnostic assays with sufficient sensitivity and specificity for use in clinical settings (Vrooman et al. (2008) Eur. Urol. 53:909-916; Van Tilborg et al. (2009) Int. J. Urol. 16:23-30; each herein incorporated by reference in its entirety).
Urothelial carcinoma comprises the most common form of BlCa, 70% of which present as papillary non-muscle-invasive tumors, although as many as 50-70% of these tumors (pTa and pT1 classified according to AJCC/UICC) (American Joint Committee on Cancer (AJCC) cancer staging manual, 6th ed., Philadelphia, Lippincott-Raven Publisher (2002); herein incorporated by reference in its entirety) will recur and approximately 10-20% will progress to invasive disease (Kaufman et al (2009) Lancet 374:239-249). To predict which patients will progress from superficial to invasive disease remains a challenge. Patients diagnosed with early-stage BlCa undergo frequent monitoring, currently based on cystoscopy and cytology, resulting in BlCa becoming one of the most costly cancer diseases to manage (Bischoff et al. (2009) Curr. Opin. Oncol. 21:272-277; herein incorporated by reference in its entirety). Better, more effective non-invasive tests for early detection of BlCa are needed to lower the morbidity and mortality associated with BlCa.